Hippocampal neurons are extremely sensitive to ischemic injury; two plausible mechanisms have been implicated in mediating such damage. The first involves overexposure of neurons to excitatory N-methyl-D-aspartate (NMDA) receptor agonists, which mobilize damaging concentrations of intracellular calcium; the second involves the generation of damaging tissue acidosis. A recent report shows that exposure to pH 6.6 can block NMDA-induced calcium currents in hippocampal neurons. This suggests that moderate acidity might protect against NMDA-mediated neurotoxicity and ischemic injury in vivo. We have observed such projection in vitro using primary hippocampal cultures. At an extracellular pH of 7.4, 6 h of glucose-free anoxia caused delayed and profound damage to neurons which was partially attenuated by the NMDA receptor antagonist, 2-amino-5-phosphonovaleric acid (APV). Dropping the pH to 6.5 provided virtually complete protection against this insult. Thus, acidosis need not be viewed exclusively as a damaging component of ischemic insults.